Stoichiometry and stability of antitumor ruthenium(II)-η 6 -p-cymene complexes of picolinic acid and its 6-methyl and 6-carboxylic acid derivatives were determined by pHpotentiometry, 1 H NMR spectroscopy and UV/Vis spectrophotometry in aqueous solution in the presence or absence of coordinating chloride ions. The picolinates form exclusively monoligand complexes in which they can coordinate via the bidentate (O,N) mode and a chloride or a water molecule is found at the third binding site of the ruthenium(II)-η 6 -p-cymene moiety depending on the conditions. [Ru(η 6 -p-cymene)(L)(H 2 O/Cl)] species are predominant at physiological pH in all studied cases. Hydrolysis of the aqua complex or the chlorido/hydroxido co-ligand exchange results in the formation of the mixed-hydroxido species [Ru(η 6 -p-cymene)(L)(OH)] in the basic pH range. There is no indication for the decomposition of the mono-ligand complexes during 24 h in the ruthenium(II)-η 6 -pcymene−picolinic acid system between pH 3 and 11; however, a slight dissociation with a low reaction rate was found in the other two systems leading to the appearance of the dinuclear trihydroxido-bridged species [Ru 2 (η 6 -p-cymene) 2 (OH) 3 ] + and free ligands at pH > 10. The replacement of the chlorido by an aqua ligand in [Ru(η 6 -p-cymene)(L)Cl] was also monitored and equilibrium constants for the exchange process were determined.
4-Hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 4-hydroxy-1,5-dimethyl-3-pyridinecarboxylic acid (DQ715) were synthesized and evaluated for possible application in iron and aluminium chelation therapy. Metal ion/ligand solution chemistry, electrochemistry, cytotoxicity and chelation efficiency in vitro were studied. The solution chemistry of each ligand with Fe-III or Al-III was investigated in aqueous NaCl solution (0.6 m) at 25 degrees C by means of potentiometric titrations, UV/Vis spectrophotometry, ESI-MS and (in the case of Al-III) by H-1 NMR measurements. Accordingly, the effects of the 5-methyl substitution of 4-hydroxy-3-pyridinecarboxylic acid on the stability of Fe and Al complexes were rationalized. Electrochemical measurements allowed to obtain the standard reduction potentials of some Fe-III/DQ715 complexes and their kinetic constants. These results indicate that Fe-III/DQ715 complexes do not redox cycle in vivo and complex formation is not kinetically limited. The lack of cytotoxicity of DQ715 was demonstrated on human embryonic kidney cells (HEK-293): the IC50 values calculated from the dose-survival curves were 1.4 (after 24 h treatment) and 0.8 mmol/L (after 48 h treatment). The treatment of cells with DQ715 in the presence of Fe-III sensibly reduced antiproliferative activity promoted by the metal ion, which suggests an Fe-III chelate effect induced by DQ715. According to our results, DQ715 is a chelator for both metal ions, whereas DQ5 is more suitable as a selective Al chelator
The interactions of Cu(II), Zn(II), and Al(III) with 1,6-dimethyl-4-hydroxy-3-pyridinecarboxylic acid (DQ716) and 2,6-dimethyl-3-hydroxy-4-pyridinecarboxylic acid (DT726), possible chelating agents in Alzheimer’s disease, were investigated in aqueous solution. The proton dissociation constants of the ligands, the stability constants, and the coordination modes of the metal complexes formed were determined by pH-potentiometric, UV–vis spectrophotometric,\ud
and 1H NMR methods. The nitrogen of the pyridine ring changes the proton affinity of the carboxylate and phenolate moieties and these pyridine derivatives form stronger complexes with Cu(II), Zn(II), and Al(III) than salicylic acid. Interactions of the ligands with human serum albumin as their potential transporter in blood were investigated at physiological pH through ultrafiltration by UV–vis and fluorescence spectroscopy
The metal ion chelators 4-hydroxy-5-methyl-3-pyridinecarboxylic acid (DQ5) and 1,5-dimethyl-4-\ud
hydroxy-3-pyridinecarboxylic acid (DQ715) and Cu(II) and Zn(II) were investigated with the aim to restore the homeostasis of the brain Cu(II) and Zn(II) in neurodegenerative diseases. The proton dissociation\ud
constants of the ligands, the stability constants, and the coordination modes of the metal complexes formed were determined by pH-potentiometric, and spectral (UV–Vis and EPR or 1H NMR) methods. The results show that in slightly acidic and neutral pH range mono and bis complexes are formed through bidentate coordination of the ligands. The biological MTT-test reveals that the DQ715 ligand is able to\ud
lower the cytotoxic effect of Cu(II) in human embryonic kidney HEK-293 cells. Our studies revealed, however, that none of the chelators were efficient enough to withdraw these metal ions from the amyloid aggregates
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